A gestational ketogenic diet alters maternal metabolic status as well as offspring physiological growth and brain structure in the neonatal mouse

BMC Pregnancy and Childbirth

Mark Henkelman¹  Jacob Ellegood¹  Dafna Sussman¹ 

[1]Mouse Imaging Centre (MICe), The Hospital for Sick Children, Toronto, Canada

关键词: CD-1 mouse;    Magnetic resonance imaging (MRI);    Mouse imaging;    Low-carbohydrate diet;    Ketogenic diet;    Neonatal brain development;   

Others  :  1132369
DOI  :  10.1186/1471-2393-13-198

 received in 2012-12-19, accepted in 2013-10-22,  发布年份 2013

【 摘 要 】

Background

The use of the ketogenic diet (KD) among women of child-bearing age has been increasing, leading to increased interest in identifying the diet’s suitability during gestation. To date, no studies have thoroughly investigated the effect of a gestational KD on offspring growth. Since ketones have been reported to play a role in cerebral lipid and myelin synthesis, it is particularly important to investigate the diet’s impact on brain anatomy of the offspring.

Methods

To fill this knowledge gap we imaged CD-1 mouse neonates whose mothers were fed either a standard diet (SD) or a KD prior to and during gestation. Images were collected at postnatal (P) 11.5 and 21.5 using Magnetic Resonance Imaging (MRI). Maternal metabolic status was also tracked during lactation, by following their body weight, blood glucose, ketone, cholesterol, and triglyceride concentrations.

Results

The KD dams exhibit a significant reduction in maternal fertility and litter size, as well as a high risk of developing fatal ketoacidosis by mid-lactation. To increase survival of the KD dams and offspring, fostering of P2.5 pups (from both KD and SD litters) by SD-foster dams was carried out. This resulted in stabilization of blood ketones of the KD dams, and aversion of the fatal ketoacidosis. We also note a slower and smaller weight loss for the KD compared with the SD dams. The average fostered KD pup exhibits retarded growth by P21.5 compared with the average fostered SD pup. An anatomical comparison of their brains further revealed significant structural differences at P11.5, and particularly at P21.5. The KD brain shows a relative bilateral decrease in the cortex, fimbria, hippocampus, corpus callosum and lateral ventricle, but a relative volumetric enlargement of the hypothalamus and medulla.

Conclusion

A gestational ketogenic diet deleteriously affects maternal fertility and increases susceptibility to fatal ketoacidosis during lactation. Prenatal and early postnatal exposure to a ketogenic diet also results in significant alterations to neonatal brain structure, and results in retarded physiological growth. These alterations could be accompanied by functional and behavioural changes in later postnatal life.

【 授权许可】

   
2013 Sussman et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

Figure 6.

【 参考文献 】

• [1]Hartman AL, Gasior M, Vining EPG, Rogawski MA: The neuropharmacology of the ketogenic diet. Pediatr Neurol 2007, 36(5):281-292.
• [2]Kossoff EH, Pyzik PL, McGrogan JR, Vining EPG, Freeman JM: Efficacy of the Ketogenic diet for infantile spasms. Pediatrics 2002, 109(5):780-783.
• [3]Van der Auwera I, Wera S, Van Leuven F, Henderson S: A ketogenic diet reduces amyloid beta 40 and 42 in a mouse model of Alzheimer’s disease. Nutr Metab 2005, 2(1):28. BioMed Central Full Text
• [4]Veech RL: The therapeutic implications of ketone bodies: the effects of ketone bodies in pathological conditions: ketosis, ketogenic diet, redox states, insulin resistance, and mitochondrial metabolism. Prostaglandins Leukot Essent Fatty Acids 2004, 70(3):309-319.
• [5]Van Itallie TB, Nufert TH: Ketones: metabolism’s ugly duckling. Nutr Rev 2003, 61(10):327-341.
• [6]Robinson AM, Williamson DH: Physiological roles of ketone bodies as substrates and signals in mammalian tissues. Physiol Rev 1980, 60(1):143-187.
• [7]Williamson DH, Buckley BM: The role of ketone bodies in brain development. In: Inborn Errors of Metabolism. New York: Academic; 1973. p. 81–96
• [8]Halestrap AP: The monocarboxylate transporter family–structure and functional characterization. IUBMB Life 2012, 64(1):1-9.
• [9]Halestrap AP, Wilson MC: The monocarboxylate transporter family–role and regulation. IUBMB Life 2012, 64(2):109-119.
• [10]Nagai A, Takebe K, Nio-Kobayashi J, Takahashi-Iwanaga H, Iwanaga T: Cellular expression of the monocarboxylate transporter (MCT) family in the placenta of mice. Placenta 2010, 31(2):126-133.
• [11]Patel MS, Srinivasan M, Aalinkeel R: Metabolic programming by nutrition during early development. Indian J Exp Biol 2000, 38(9):849-855.
• [12]Rudolf MC, Sherwin RS: Maternal ketosis and its effects on the fetus. Clin Endocrinol Metab 1983, 12(2):413-428.
• [13]Jones CT, Rolph TP: Metabolism during fetal life: a functional assessment of metabolic development. Physiol Rev 1985, 65(2):357-430.
• [14]Watson RE, Desesso JM, Hurtt ME, Cappon GD: Postnatal growth and morphological development of the brain: a species comparison. Birth Defects Res B Dev Reprod Toxicol 2006, 77(5):471-484.
• [15]Levitt P: Structural and functional maturation of the developing primate brain. J Pediatr 2003, 143(4):35-45.
• [16]Sussman D, van Eede M, Wong MD, Adamson SL, Henkelman RM: Effects of a Ketogenic diet during pregnancy on embryonic growth in the mouse. BMC Pregnancy Childbirth 2013, 13:109. BioMed Central Full Text
• [17]Zhang J, Richards LJ, Miller MI, Yarowsky P, van Zijl P, Susumu M: Characterization of mouse brain and its development using diffusion tensor imaging and computational techniques. In Engineering in Medicine and Biology Society (EMBS), 28th Annual International Conference of the IEEE, Aug. 30 2006-Sept. 3,. New York, NY: Conf Proc IEEE Eng Med Biol Soc; 2006:2252-2255.
• [18]Dangata YY, Findlater GS, Kaufman MH: Postnatal development of the optic nerve in (C57BL x CBA)F1 hybrid mice: general changes in morphometric parameters. J Anat 1996, 189(Pt 1):117.
• [19]Harlan: Teklad Lab animal diets. [http://www.harlan.com/online_literature/teklad_lab_animal_diets webcite]
• [20]Abbott: Precision Xtra system product specifications. [http://www.abbottdiabetescare.ca/ webcite]
• [21]Girden ER: ANOVA: Repeated Measures. Newbury Park, CA: Sage University Paper Series on Quantitative Applications in the Social Sciences; 1992.
• [22]Spring S, Lerch JP, Henkelman RM: Sexual dimorphism revealed in the structure of the mouse brain using three-dimensional magnetic resonance imaging. Neuroimage 2007, 35(4):1424-1433.
• [23]Jones DK, Horsfield MA, Simmons A: Optimal strategies for measuring diffusion in anisotropic systems by magnetic resonance imaging. Magn Reson Med 1999, 42(3):515-525.
• [24]Le Bihan D, Mangin JF, Poupon C, Clark CA, Pappata S, Molko N, Chabriat H: Diffusion tensor imaging: concepts and applications. J Magn Reson Imaging 2001, 13(4):534-546.
• [25]Ellegood J, Pacey LK, Hampson DR, Lerch JP, Henkelman RM: Anatomical phenotyping in a mouse model of fragile X syndrome with magnetic resonance imaging. Neuroimage 2010, 53(3):1023-1029.
• [26]Avants BB, Yushkevich P, Pluta J, Minskoff D, Korczykowski M, Detre J, Gee JC: The optimal template effect in hippocampus studies of diseased populations. Neuroimage 2010, 49:2457-2466.
• [27]Collins DL, Neelin P, Peters TM, Evans AC: Automatic 3D intersubject registration of MR volumetric data in standardized Talairach space. J Comput Assist Tomogr 1994, 18:192-205.
• [28]Benjamini Y, Hochberg Y: Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc Series B (Methodological) 1995, 57(1):289-300.
• [29]Benjamini Y: Discovering the false discovery rate. J R Stat Soc Series B (Statistical Methodology) 2010, 72(4):405-416.
• [30]Dorr AE, Lerch JP, Spring S, Kabani N, Henkelman RM: High resolution three-dimensional brain atlas using an average magnetic resonance image of 40 adult C57Bl/6J mice. Neuroimage 2008, 42(1):60-9.
• [31]Goettsch M: Comparative protein requirements of the rat and mouse for growth, reproduction and lactation using casein diets. J Nutr 1960, 70:307-312.
• [32]Mavropoulos J, Yancy W, Hepburn J, Westman E: The effects of a low-carbohydrate, ketogenic diet on the polycystic ovary syndrome: A pilot study. Nutr Metabolism 2005, 2(1):35. BioMed Central Full Text
• [33]Derrickson EM: The effects of dietary protein levels on milk protein levels and postnatal growth in laboratory mice (Mus musculus). J Mammal 2007, 88(6):1475-1481.
• [34]Weber EM: Maternal behaviour in Mus musculus sp.: an ethological review. Appl Anim Behav Sci 2008, 114(1-2):1-22.
• [35]Bondrup-Nielsen S, Foley PM: Long-term effects of malnutrition on reproduction: a laboratory study with meadow voles, Microtus pennsylvanicus, and red-backed voles, Clethrionomys gapperi. Can J Zool 1994, 72(2):232-238.
• [36]Schams D: Hormonal Control of Lactation. In: Breast-feeding and the mother. London, England: Ciba Foundation; 1976. 27-48. (Ciba Foundation Symposium, New Series No. 45)
• [37]Wilde CJ, Knight CH, Flint DJ: Control of milk secretion and apoptosis during mammary involution. J Mammary Gland Biol Neoplasia 1999, 4(2):129-136.
• [38]Seyfried T: Cancer as a Metabolic Disease: On the Origin, Management, and Prevention of Cancer. Hoboken, New Jersey: John Wiley & Sons; 2012.
• [39]Smith DM: The effect of daily separation of sows from their litters upom milk yield, creep intake, and energetic efficiency. N Z J Agri Res 1961, 4:232-245.
• [40]Richert MM, Schwertfeger KL, Ryder JW, Anderson SM: An atlas of mouse mammary gland development. J Mammary Gland Biol Neoplasia 2000, 5(2):227-241.
• [41]Kent JC, Mitoulas L, Cox DB, Owens RA, Hartmann PE: Breast volume and milk production during extended lactation in women. Exp Physiol 1999, 84(2):435-447.
• [42]Cleal JK, Poore KR, Boullin JP, Khan O, Chau R, Hambidge O, Torrens C, Newman JP, Poston L, Noakes DE, Hanson MA, Green LR: Mismatched pre- and postnatal nutrition leads to cardiovascular dysfunction and altered renal function in adulthood. Proc Nat Acad Sci 2007, 104(22):9529-9533.
• [43]Morgane PJ: Prenatal malnutrition and development of the brain. Neurosci Biobehav Rev 1993, 17(1):91-128.
• [44]Cahill Jr GF: Ketosis. Kidney Int 1981, 20(3):416-425.
• [45]Shambaugh 3rd GE, Angulo MC, Koehler RR: Fetal fuels. VII. Ketone bodies inhibit synthesis of purines in fetal rat brain. Am J Physiol 1984, 247(1 Pt 1):E111-117.
• [46]Shambaugh 3rd GE: Ketone body metabolism in the mother and fetus. Fed Proc 1985, 44(7):2347-2351.
• [47]Veech RL, Chance B, Kashiwaya Y, Lardy HA, Cahill Jr GF: Ketone bodies, potential therapeutic uses. IUBMB Life 2001, 51(4):241-247.
• [48]Yudkoff M, Daikhin Y, Nissim I, Horyn O, Lazarow A, Luhovyy B, Wehrli S, Nissim I: Response of brain amino acid metabolism to ketosis. Neurochem Int 2005, 47(1-2):119-128.
• [49]Rosebrough RW, Steele NC, Frobish LT: Effect of ketogenic diets in gestation on some characteristics of carbohydrate metabolism in fetal pig brain and liver. Growth 1981, 45(1):42-57.
• [50]Williamson DH: Utilization of ketone bodies by mammalian tissues. Biochem Soc Trans 1981, 9(4):346-7.
• [51]Morris AAM: Cerebral ketone body metabolism. J Inherit Metab Dis 2005, 28(2):109-121.
• [52]Lust WD, Pundik S, Zechel J, Zhou Y, Buczek M, Selman WR: Changing metabolic and energy profiles in fetal, neonatal, and adult rat brain. Metab Brain Dis 2003, 18(3):195-206.